The details of this collaborative study between Johns Hopkins, Stanford and Harvard appear August 15 in the early online publication of Nature.
The researchers, using blood-forming stem cells from mice, focused their investigation specifically on an epigenetic mark known as methylation. This change is found in one of the building blocks of DNA, is remembered by a cell when it divides, and often is associated with turning off genes.
Employing a customized genome-wide methylation-profiling method dubbed CHARM (comprehensive high-throughput arrays for relative methylation), the team analyzed 4.6 million potentially methylated sites in a variety of blood cells from mice to see where DNA methylation changes occurred during the normal differentiation process. The team chose the blood cell system as its model because it’s well-understood in terms of cellular development.
They looked at eight types of cells in various stages of commitment, including very early blood stem cells that had yet to differentiate into red and white blood cells. They also looked at cells that are more committed to differentiation: the precursors of the two major types of white blood cells, lymphocytes and myeloid cells. Finally, they looked at older cells that were close to their ultimate fates to get more complete pictures of the precursor-progeny relationships — for example, at white blood cells that had gone fairly far in T-cell lymphocyte development. (Lymphoid and myeloid constitute the two major types of progenitor blood cells.)
“It wasn’t a complete tree, but it was large portions of the tree, and different branches,” says Andrew Feinberg, M.D., M.P.H., King Fahd Professor of Molecular Medicine and director of the Center for Epigenetics at Hopkins’ Institute for Basic Biomedical Sciences.
“Genes themselves aren’t going to tell us what’s really responsible for the great diversity in cell types in a complex organism like ourselves,” Feinberg says. “But I think epigenetics—and how it controls genes-can. That’s why we wanted to know what was happening generally to the levels of DNA methylation as cells differentiate.”
One of the surprising finds was how widely DNA methylation patterns vary in cells as they differentiate. “It wasn’t a boring linear process,” Feinberg says. “Instead, we saw these waves of change during the development of these cell types.”
The data shows that when all is said and done, the lymphocytes had many more methylated genes than myeloid cells. However, on the way to becoming highly methylated, lymphocytes experience a huge wave of loss of DNA methylation early in development and then a regain of methylation. The myeloid cells, on the other hand, undergo a wave of increased methylation early in development and then erase that methylation later in development.
Rudimentary as it is, this first epigenetic landscape map has predictive power in the reverse direction, according to Feinberg. The team could tell which types of stem cells the blood cells had come from, because epigenetically those blood cells had not fully let go of their past; they had residual marks that were characteristic of their lineage.
This project involved a repertoire of talents..“None of whom were more integral than Irv Weissman at Stanford,” Feinberg says. “He’s a great stem cell biologist and he lent a whole level of expertise that we didn’t have.”
One apparent application of this work might be to employ these same techniques to assess how completely an induced pluripotent stem cell (iPSC) has been reprogrammed.
“You might want to have an incompletely reprogrammed cell type from blood, for example, that you take just to a certain point because then you want to turn it into a different kind of blood cell,” Feinberg says, cautioning that the various applications are strictly theoretical.
Because the data seem to indicate discreet stages of cell differentiation characterized by waves of changes in one direction and subsequent waves in another, cell types conceivably could be redefined according to epigenetic marks that will provide new insights into both normal development and disease processes.“Leukemias and lymphomas likely involve disruptions of the epigenetic landscape,” Feinberg says. “As epigenetic maps such as this one begin to get fleshed out by us and others, they will guide our understanding of why those diseases behave the way they do, and pave the way for new therapies.”
The research was supported by the National Institutes of Health and a grant from the Thomas and Stacey Siebel Foundation.Johns Hopkins authors, in addition to Feinberg, are Hong Ji, Peter Murakami, Akiko Doi, Hwajin Lee, Martin J. Aryee, and Rafael A. Irizarry.
Other authors are Lauren I. R. Ehrlich, Jun Seita, Paul Lindau, Derrick J Rossi, Matthew A. Inlay, Thomas Serwold, Holger Karsunky, Lena Ho, and Irving L. Weissman, all of Stanford University; and Kitai Kim and George Q. Daley, both of Harvard University.On the Web:
Maryalice Yakutchik | Newswise Science News
Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München
Second research flight into zero gravity
21.10.2016 | Universität Zürich
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences